U.S. patent application number 09/767306 was filed with the patent office on 2002-03-28 for thiazolidinecarboxyl acids.
Invention is credited to Friebe, Walter-Gunar, Krell, Hans-Willi, Woelle, Sabine, Wolff, Hans-Peter.
Application Number | 20020037901 09/767306 |
Document ID | / |
Family ID | 8167761 |
Filed Date | 2002-03-28 |
United States Patent
Application |
20020037901 |
Kind Code |
A1 |
Friebe, Walter-Gunar ; et
al. |
March 28, 2002 |
Thiazolidinecarboxyl acids
Abstract
5-Arylidene-4-oxo-2-thioxo-3-thiazolidinecarboxylic acids of
formula I 1 in which the symbols R.sup.1, R.sup.2, A, A.sup.1 and
A.sup.2 have the significance given in the description as
medicaments for the treatment of cancer diseases.
Inventors: |
Friebe, Walter-Gunar;
(Mannheim, DE) ; Krell, Hans-Willi; (Penzberg,
DE) ; Woelle, Sabine; (Penzberg, DE) ; Wolff,
Hans-Peter; (Weinheim, DE) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.
PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
|
Family ID: |
8167761 |
Appl. No.: |
09/767306 |
Filed: |
January 23, 2001 |
Current U.S.
Class: |
514/252.05 ;
514/256; 514/342; 514/369; 544/238; 544/242; 546/270.4 |
Current CPC
Class: |
C07D 277/20 20130101;
A61P 35/00 20180101; C07D 417/14 20130101; C07D 417/12
20130101 |
Class at
Publication: |
514/252.05 ;
514/256; 514/342; 514/369; 544/238; 544/242; 546/270.4 |
International
Class: |
A61K 031/50; A61K
031/501; A61K 031/505; A01N 043/54; A61K 031/44; A01N 043/40; A61K
031/425; A01N 043/78 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 3, 2000 |
EP |
00102097.3 |
Claims
1. A compound of formula I: 12wherein A is a linear
C.sub.1-C.sub.6-alkylene chain or a group >CHR, wherein R is a
C.sub.1-C.sub.6-alkyl residue, an aryl residue, an aralkyl residue
or a carboxyalkyl residue, A.sup.1 and A.sup.2 each independently
in any combination are a linear or branched saturated or
unsaturated C.sub.1-C.sub.6-alkylene chain, R.sup.1 and R.sup.2
each independently in any combination are a group of formula II,
formula III or formula IV, 13wherein X is an oxygen or sulphur atom
and each Y independently is a nitrogen or carbon atom, with the
proviso that both Y's can not simultaneously be nitrogen, Z is a
C.sub.1-C.sub.4-alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,
C.sub.3-C.sub.5-alkenyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkylthio, acylamino, (alkyl)aminocarbonyl,
C.sub.1-C.sub.4-alkyl-carbonyl, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, trifluoromethylthio, nitro, hydroxy or carboxy
group or a chlorine, bromine or fluorine atom or the aromatic ring
in formulae II-IV is substituted with a methylenedioxy or
ethylenedioxy group and n is a whole number between 0 and 3,
whereby the Z substituents can be present in any positions, with
the proviso that the R.sup.1-A.sup.1- and R.sup.2-A.sup.2- residues
can not simultaneously be an unsubstituted benzyl residue when A is
a methylene group, or a pharmaceutically acceptable salt or ester
of a compound of formula I, or a position isomer, optically active
form, racemate or diastereomer mixture thereof.
2. A compound in accordance with claim 1, wherein A is a linear
C.sub.1-C.sub.6-alkylene chain or a group >CH(R).
3. A compound in accordance with claim 2, wherein the compound is
present in the (R) or (S) configuration or as a racemate when R is
a linear C.sub.1-C.sub.6-alkyl residue, an aryl residue, an aralkyl
residue or a carboxyalkyl residue.
4. A compound in accordance with claim 1, wherein R.sup.1-A.sup.1-
and R.sup.2-A.sup.2- are independently an aralkyl group with a
C.sub.1-C.sub.4-alkylene chain, a cinnamyl residue, a
2-thienylmethyl, a 3-thienylmethyl, a 2-furanylmethyl, a
3-furanylmethyl, a 2-thiazolylmethyl, a 4-thiazolylmethyl, a
2-oxazolylmethyl, a 4-oxazolylmethyl, a 3-isoxazolylmethyl or a
4-isoxazolylmethyl group or a homologue thereof with
C.sub.2-C.sub.4-alkylene chains, whereby the respective aryl and
heteroaryl residues of the aforementioned groups are unsubstituted
or mono- or multiply-substituted by a substituent selected from
Z.
5. A compound in accordance with claim 1, wherein R.sup.1 and
R.sup.2 each independently are a benzyl group, a 2-phenethyl group,
a 3-phenylpropyl group or a group of formula III or IV, wherein the
groups A.sup.1 and A.sup.2 are methylene, 1,2-ethanediyl or
1,3-propanediyl and A is methylene, phenylmethylene,
2-phenylethane-1,1-diyl, 1,2-ethanediyl or 1,3-propanediyl, whereby
the respective aryl and heteroaryl groups are unsubtistuted or
substituted by a substituent selected from Z.
6. A compound in accordance with claim 1,
5-[(2,4-bis-(4-methylphenylmetho-
xy)phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid.
7. A compound in accordance with claim 1,
5-[(2,5-bis-(4-methylphenylmetho-
xy)phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid.
8. A compound in accordance with claim 1,
5-[(2,5-bis-(3-(4-chlorophenyl)p-
ropoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidineacetic
acid.
9. A compound in accordance with claim 1,
5-[(2-phenylmethoxy-5-(3-phenylp-
ropoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidineacetic
acid.
10. A compound in accordance with claim 1,
5-[(2-(2-thienylmethoxy)-5-(3-p-
henylpropoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidineacetic
acid.
11. A compound in accordance with claim 1,
2-{5-[(2,4-bis-(4-methylphenylm-
ethoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidine}-2-phenylacetic
acid.
12. A compound in accordance with claim 1,
2-{5-[(2,4-bis-(4-methylphenylm-
ethoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidine}-3-phenypropionic
acid.
13. A compound in accordance with claim 1,
2-{5-[(2,4-bis-(4-methylphenyl--
methoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidine}-2-(4-chlorophenyl-
)acetic acid.
14. A method of reducing or preventing tumor growth and the
metastasis of tumours, comprising administering to a patient in
need of such treatment or prevention an effective amount of a
compound of formula I, 14in which A is a linear
C.sub.1-C.sub.6-alkylene chain or a group >CHR, wherein R is a
C.sub.1-C.sub.6-alkyl residue, an aryl residue, an aralkyl residue
or a carboxyalkyl residue, A.sup.1 and A.sup.2 each independently
in any combination are a linear or branched saturated or
unsaturated C.sub.1-C.sub.6-alkylene chain, R.sup.1 and R.sup.2
each independently in any combination are a group of formula II,
formula III or formula IV, 15wherein X is an oxygen or sulphur atom
and each Y is a nitrogen or carbon atom, with the proviso that both
Y's can not simultaneously be nitrogen, Z is a
C.sub.1-C.sub.4-alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,
C.sub.3-C.sub.5-alkenyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkylthio, acylamino, (alkyl)aminocarbonyl,
C.sub.1-C.sub.4-alkyl-carbonyl, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, trifluoromethylthio, nitro, hydroxy or carboxy
group or a chlorine, bromine or fluorine atom or the aromatic ring
in formulae II-IV is substituted with a methylenedioxy or
ethylenedioxy group and n is a whole number between 0 and 3,
whereby the Z substituents can be present in any positions, or a
pharmaceutically acceptable salt or ester of a compound of formula
I, or a position isomer, optically active form, racemate or
diastereomer mixture thereof.
15. A compound in accordance with claim 14, wherein A is a linear
C.sub.1-C.sub.6-alkylene chain or a group >CH(R).
16. A compound in accordance with claim 15, wherein the compound is
present in the (R) or (S) configuration or as a racemate when R is
a linear C.sub.1-C.sub.6-alkyl residue, an aryl residue, an aralkyl
residue or a carboxyalkyl residue.
17. A compound in accordance with claim 14, wherein
R.sup.1-A.sup.1- and R.sup.2-A.sup.2- are independently an aralkyl
group with a C.sub.1-C.sub.4-alkylene chain, a cinnamyl residue, a
2-thienylmethyl, a 3-thienylmethyl, a 2-furanylmethyl, a
3-furanylmethyl, a 2-thiazolylmethyl, a 4-thiazolylmethyl, a
2-oxazolylmethyl, a 4-oxazolylmethyl, a 3-isoxazolylmethyl or a
4-isoxazolylmethyl group or a homologue thereof with
C.sub.2-C.sub.4-alkylene chains, whereby the respective aryl and
heteroaryl residues of the aforementioned groups are unsubstituted
or mono- or multiply-substituted by a substituent selected from
Z.
18. A compound in accordance with claim 14, wherein R.sup.1 and
R.sup.2 each independently are a benzyl group, a 2-phenethyl group,
a 3-phenylpropyl group or a group of formula III or IV, wherein the
groups A.sup.1 and A.sup.2 are methylene, 1,2-ethanediyl or
1,3-propanediyl and A is methylene, phenylmethylene,
2-phenylethane-1.1-diyl, 1,2-ethanediyl or 1,3-propanediyl, whereby
the respective aryl and heteroaryl groups are unsubtistuted or
substituted by a substituent selected from Z.
19. A compound in accordance with claim 14,
5-[(2,4-bis-(4-methylphenylmet-
hoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidineacetic
acid.
20. A compound in accordance with claim 14,
5-[(2,5-bis-(4-methylphenylmet-
hoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidineacetic
acid.
21. A compound in accordance with claim 14,
5-[(2,5-bis-(3-(4-chlorophenyl-
)propoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidineacetic
acid.
22. A compound in accordance with claim 14,
5-[(2-phenylmethoxy-5-(3-pheny-
lpropoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidineacetic
acid.
23. A compound in accordance with claim 14,
5-[(2-(2-thienylmethoxy)-5-(3--
phenylpropoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidineacetic
acid.
24. A compound in accordance with claim 14,
2-{5-[(2,4-bis-(4-methylphenyl-
methoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidine}-2-phenylacetic
acid.
25. A compound in accordance with claim 14,
2-{5-[(2,4-bis-(4-methylphenyl- methoxy)phenyl)
methylene]-4-oxo-2-thioxo-3-thiazolidine}-3-phenypropionic
acid.
26. A compound in accordance with claim 14,
2-{5-[(2,4-bis-(4-methylphenyl-
methoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidine}-2-(4-chlorophenyl-
)acetic acid.
Description
FIELD OF THE INVENTION
[0001] The object of the present invention are
thiazolidinecarboxylic acids, a process for their manufacture and
medicaments which contain these compounds as well as the use of
these compounds in the production of medicaments.
BACKGROUND OF THE INVENTION
[0002] Plasmin is a key enzyme for the dissolution of the
extracellular matrix, which occurs especially at contact sites of
cells to an increasing extent. A strong expression of the uPA/uPAR
system takes place especially in tumour cells (N. Behrendt et al.,
Fibrinolysis & Proteolysis, 1998, 12(4): The urokinase
receptor). By the induction of the strong proteolytically active
uPA(urokinase type Plasminogen Activator)/uPAR (membrane-bound
urokinase receptor) system it is possible to spread the tumour
cells in the body by dissolution of the extracellular matrix as a
result of plasmin liberation (P. A. Andreasen et al., Int. J.
Cancer, 1997,72: The urokinase-type plasminogen activator system in
cancer metastasis: a review). A correlation of the increased
expression rate of the uPA/uPAR system with an increased
metastasing rate has been demonstrated in patients with different
tumour diseases (e.g. R.Hewitt et al., Enzyme Protein, 1996,49:
Stromal cell expression of components of matrix-degrading protease
systems in human cancer). A significant reduction in tumour growth
can be achieved in animal experiments with tumour cell lines in
mice by blocking the uPAR system with monoclonal antibodies.
[0003] In the literature there are already described numerous
5-arylidene-rhodanine-carboxylic acids which differ from the
compounds in accordance with the present invention in that the
substitution of the phenyl ring differs distinctly from that of the
present invention. IN particular,
5-(2,4-bis-benzyloxybenzylidene)rhodanineacetic acid and
5-(3,4-bis-benzyloxybenzylidene)-rhodanineacetic acid and their use
for the prophylaxis of maturity onset diabetes are described in
Patent Application DE 4318550. A connection between the prophylaxis
of maturity onset diabetes and inhibiting the binding of uPA to
uPAR, thereby preventing an activation of plasminogen to plasmin,
does not exist. In fact, other compounds from Patent Application DE
4318550, which are especially valuable for the treatment of
maturity onset diabetes, showed no activity in inhibiting the
binding of uPA to uPAR, thereby preventing an activation of
plasminogen to plasmin.
BRIEF SUMMARY OF THE INVENTION
[0004] The invention relates to a compound of formula I: 2
[0005] wherein
[0006] A is a linear C.sub.1-C.sub.6-alkyl chain or a group
>CHR, wherein R is a C.sub.1-C.sub.6-alkyl residue, an aryl
residue, an aralkyl residue or a carboxyalkyl residue,
[0007] A and A.sup.2
[0008] each independently in any combination are a linear or
branched saturated or unsaturated C.sub.1-C.sub.6-alkylene
chain,
[0009] R.sup.1 and R.sup.2
[0010] each independently in any combination are a group of formula
II, formula III or formula IV, 3
[0011] wherein X is an oxygen or sulphur atom and each Y
independently is a nitrogen or carbon atom, with the proviso that
both Y's can not simultaneously be nitrogen,
[0012] Z is a C.sub.1-C.sub.4-alkyl, aryl, aralkyl, heteroaryl,
heteroaralkyl, C.sub.3-C.sub.5-alkenyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkylthio, acylamino, (alkyl)aminocarbonyl,
C.sub.1-C.sub.4-alkyl-carbonyl, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, trifluoromethylthio, nitro, hydroxy or carboxy
group or a chlorine, bromine or fluorine atom
[0013] or the aromatic ring in formulae II-IV is substituted with a
methylenedioxy or ethylenedioxy group and
[0014] n is a whole number between 0 and 3,
[0015] whereby the Z substituents can be present in any
positions,
[0016] with the proviso that the R.sup.1-A.sup.1- and
R.sup.2-A.sup.2-residues can not simultaneously be an unsubstituted
benzyl residue when A is a methylene group, or a
[0017] pharmaceutically acceptable salt or ester of a compound of
formula I, or a position isomer, optically active form, racemate or
diastereomer mixture thereof.
[0018] In another aspect, the invention relates to a method of
preventing tumour growth or metastasis, comprising administering to
a patient in need of such treatment or prevention an effective
amount of a compound of formula I, 4
[0019] in which
[0020] A is a linear C.sub.1-C.sub.6-alkylene chain or a group
>CHR, wherein R is a C.sub.1-C.sub.6-alkyl residue, an aryl
residue, an aralkyl residue or a carboxyalkyl residue,
[0021] A.sup.1 and A.sup.2
[0022] each independently in any combination are a linear or
branched saturated or unsaturated C.sub.1-C.sub.6-alkylene
chain,
[0023] R.sup.1 and R.sup.2
[0024] each independently in any combination are a group of formula
II, formula III or formula IV, 5
[0025] wherein X is an oxygen or sulphur atom and each Y is a
nitrogen or carbon atom, with the proviso that both Y's can not
simultaneously be nitrogen,
[0026] Z is a C.sub.1-C.sub.4-alkyl, aryl, aralkyl, heteroaryl,
heteroaralkyl, C.sub.3-C.sub.5-alkenyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkylthio, acylamino, (alkyl)aminocarbonyl,
C.sub.1-C.sub.4-alkyl-carbonyl, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, trifluoromethylthio, nitro, hydroxy or carboxy
group or a chlorine, bromine or fluorine atom
[0027] or the aromatic ring in formulae II-IV is substituted with a
methylenedioxy or ethylenedioxy group and
[0028] n is a whole number between 0 and 3,
[0029] whereby the Z substituents can be present in any
positions,
[0030] or a pharmaceutically acceptable salt or ester of a compound
of formula I, or a position isomer, optically active form, racemate
or diastereomer mixture thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0031] The invention is concerned with the use of
5-arylidene-4-oxo-2-thio- xo-3-thiazolidine-carboxylic acids of
formula I 6
[0032] as medicaments for the treatment of cancer diseases,
especially for the prevention of the growth and the metastasing of
tumors,
[0033] in which
[0034] A signifies a linear C.sub.1-C.sub.6-alkylene chain or a
group >CHR, wherein R signifies a C.sub.1-C.sub.6-alkyl residue,
an aryl residue, an aralkyl residue or a carboxyalkyl residue,
[0035] A.sup.1 and A.sup.2
[0036] each independently in any combination signify a linear or
branched saturated or unsaturated C.sub.1-C.sub.6-alkylene
chain,
[0037] R.sup.1 and R.sup.2
[0038] each independently in any combination signify a group of
general formula II to IV, 7
[0039] wherein X signifies an oxygen or sulphur atom and each Y
independently signifies a nitrogen or carbon atom, with the proviso
that both Y's can not simultaneously signify nitrogen,
[0040] Z signifies a C.sub.1-C.sub.4-alkyl, aryl, aralkyl,
heteroaryl, heteroaralkyl, C.sub.3-C.sub.5-alkenyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkylthio, acylamino,
(alkyl)aminocarbonyl, C.sub.1-C.sub.4-alkyl-carbonyl,
trifluoromethyl, difluoromethoxy, trifluoromethoxy,
trifluoromethylthio, nitro, hydroxy or carboxy group or a chlorine,
bromine or fluorine atom or the aromatic ring in formulae II-IV is
substituted with a methylenedioxy or ethylenedioxy group and
[0041] n is a whole number between 0 and 3,
[0042] whereby the Z substituents can be present in any
positions,
[0043] as well as compounds of formula I in which the symbols A,
R.sup.1, R.sup.2, A.sup.1, A.sup.2, Z and n have the significance
set forth above, with the proviso that the R.sup.1-A.sup.1- and
R.sup.2-A.sup.2- residues can not simultaneously signify an
unsubstituted benzyl residue when A is a methylene group, and their
use as medicaments for the treatment of cancer diseases, especially
for the prevention of the growth and the metastasing of
tumours.
[0044] Objects of this invention are also physiologically
compatible salts or esters of formula I as well as the position
isomers, the optically active forms, the racemates and the
diastereomer mixtures of these compounds.
[0045] It has surprisingly been found that the compounds of formula
I have valuable pharmacological properties. In particular, they
inhibit the binding of uPA (urokinase type Plasminogen Activator)
to the membrane-bound urokinase receptor (uPAR) and thereby prevent
an activation of plasminogen to plasmin.
[0046] Accordingly, the compounds in accordance with the invention
are valuable, low molecular weight, orally administerable
medicaments for the prophylaxis and treatment of cancer diseases,
which are especially suitable for preventing the growth and the
metastasing of tumours.
[0047] In formulae I-IV the C.sub.1-C.sub.4-alkyl residues, the
C.sub.1-C.sub.6-alkyl residues and the C.sub.3-C.sub.5-alkenyl
residues can be straight-chain or branched. Preferably, the methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl,
hexyl, allyl and isopropenyl residues are to be understood
thereunder.
[0048] As C.sub.1-C.sub.6-alkylene chains of residues A.sup.1 and
A.sup.2 there preferably come into consideration the methylene, the
1,2-ethanediyl, the 1,3-propanediyl and the 1,4-butanediyl
group.
[0049] The groups of formula III are preferably thienyl, furanyl,
isoxazolyl, thiazolyl and oxazolyl. The groups of formula IV are
preferably pyridinyl and pyrimidinyl.
[0050] As the alkyl residue in the Z substituents there is to be
understood lower alkyl with 1-4 carbon atoms, especially the
methyl, ethyl, isopropyl and tert.butyl residue. Preferred Z
residues are, furthermore, the phenyl, 2-thienyl, 3-thienyl,
methoxy, trifluoromethyl, trifluoromethoxy, methylthio and
acylamino groups as well as the halogen atoms chlorine, fluorine
and bromine. Acyl residues are preferably acetyl and propionyl. The
phenyl and thienyl residues can be substituted with one or two
residues, whereby these residues can be the same as or different to
one another and can be a lower alkyl, lower alkoxy, nitro,
(di)(alkyl)amino, trifluoromethyl or hydroxy group or halogen.
Under halogen there is to be understood here fluorine, bromine and
especially chlorine.
[0051] Under the C.sub.1-C.sub.6-alkylene chains of residue A there
are to be understood especially the methylene, the 1,2-ethanediyl,
the 1,3-propanediyl and the 1,4-butanediyl residue.
[0052] An aryl residue present as the substituent R in >CH(R)
for A signifies phenyl which can be unsubstituted or substituted
with one or two residues, whereby these residues can be the same as
or different to one another and can be a lower alkyl group, lower
alkoxy group, hydroxy group or halogen. Under halogen there is to
be understood here fluorine, bromine and especially chlorine.
Aralkyl for the same substituent denotes an aryl residue as
previously defined linked by a C.sub.1-C.sub.6-alkylen- e group as
defined above. A carboxyalkyl residue preferably signifies the
group --(CH.sub.2).sub.m--COOH and m=1-3.
[0053] Preferred compounds of formula I are compounds in which A is
either a linear C.sub.1-C.sub.6-alkylene chain or a group
>CH(R), whereby the compounds in question can be present in the
(R) or (S) configuration or as the racemate when R signifies a
linear C.sub.1-C.sub.6-alkyl residue, an aryl residue, an aralkyl
residue or a carboxyalkyl residue.
[0054] Preferred compounds are, furthermore, compounds in which
R.sup.1-A.sup.1- and R.sup.2-A.sup.2- are the same as or different
to one another and in each case signify an aralkyl group with a
C.sub.1-C.sub.4-alkylene chain, a cinnamyl residue, a
2-thienylmethyl, a 3-thienylmethyl, a 2-furanylmethyl, a
3-furanylmethyl, a 2-thiazolylmethyl, a 4-thiazolylmethyl, a
2-oxazolylmethyl, a 4-oxazolyl-methyl, a 3-isoxazolylmethyl or a
4-isoxazolylmethyl group or homologue thereof with
C.sub.2-C.sub.4-alkylene chains, whereby the respective aryl and
heteroaryl residues of the aforementioned groups can be mono- or
multiply-substituted by one of the Z substituents defined
above.
[0055] Especially preferred sub-groups of compounds of general
formula I are compounds in which R.sup.1 and R.sup.2 each
independently signify benzyl groups, 2-phenethyl groups,
3-phenyl-propyl groups or groups of general formulae III and IV,
wherein the groups A.sup.1 and A.sup.2 are methylene,
1,2-ethanediyl or 1,3-propanediyl and A signifies methylene,
phenylmethylene, 2-phenylethane-1,1-diyl, 1,2-ethanediyl or
1,3-propanediyl, whereby the aryl and heteroaryl groups are
optionally substituted by the Z substituents set forth above.
[0056] Examples of physiologically usable salts of the compounds of
formula I are salts with physiologically compatible bases. Examples
of such salts are alkali metal, alkaline earth metal, ammonium and
alkylammonium salts, such as the Na, K, Ca or tetramethylammonium
salt.
[0057] The separation of the racemates into the enantiomers can be
carried out by analytical, semi-preparative and preparative
chromatography on suitable optically active phases with
conventional elution agents.
[0058] Suitable optically active phases are, for example, optically
active polyacrylamides or polymethacrylamides and to some extent
also silica gel (e.g. ChiraSpher.RTM. from Merck, Chirapak.RTM.
OT/OP from Baker), cellulose esters/carbamates (e.g. Chiracel.RTM.
OB/OY from Baker/Diacel), phases based on cyclodextrins or crown
ethers (e.g. Crownpak.RTM. from Diacel) or microcrystalline
cellulose triacetate (Merck).
[0059] Enantiomers of compounds of formula I can also be obtained
by using the respective optically active starting material for the
synthesis of the compounds.
[0060] The compounds of general formula I in which R.sup.1,
R.sup.2, A, A.sup.1, A.sup.2, Z and n have the significances set
forth above are manufactured by condensing an aromatic aldehyde of
formula V 8
[0061] in which R.sup.1, R.sup.2, A.sup.1 and A.sup.2 have the
significances set forth above,
[0062] with a rhodaninecarboxylic acid derivative of formula VI
9
[0063] in which A has the significance set forth above and R.sup.1
signifies hydrogen or a lower alkyl residue,
[0064] in a known manner known to give a compound of formula I or
VII 10
[0065] and, if desired, saponifying the ester group OR.sup.3 in a
compound of formula VII according to known methods.
[0066] The condensation is usually carried out in the presence of a
catalytic amount of a base such as sodium acetate or pyridine. In
accordance with the invention piperidine acetate is used as the
catalyst under water-withdrawing conditions, for example in the
presence of water-binding reagents such as molecular sieve or
sodium sulphate or by azeotropic withdrawal of water.
[0067] The saponification of an ester of formula VII can be carried
out not only under acidic conditions, but also under basic
conditions. Preferably, the esters are saponified by treatment with
1N potassium hydroxide solution in methanol at 40.degree. C.
[0068] A further known method for the manufacture of the compounds
of formula I in which R.sup.1, R.sup.2, A, A.sup.1, A.sup.2, Z and
n have the significances set forth above comprises the condensation
of compounds of formula V with rhodanine to give compounds of
formula VIII 11
[0069] and subsequent alkylation with compounds of formula IX
W--A--COOR.sup.3 (IX),
[0070] in which W signifies a reactive group such as chlorine,
bromine, methylsulphonyloxy or p-toluenesulphonyloxy and R.sup.3
has the significance given above, to give compounds of formula I or
VII.
[0071] The alkylations are usually carried out with the addition of
an acid-binding agent such as e.g. sodium acetate, triethylamine or
potassium carbonate in a polar or non-polar solvent, preferably in
dimethylformamide or methylene chloride, at temperatures between
-40.degree. C. and the boiling point of the chosen solvent.
Preferably, an alkali salt of compounds of formula VIII and a free
acid of formula IX, wherein W signifies bromine or chlorine and
R.sup.3 signifies hydrogen, are used for the alkylation in the
presence of excess alkali.
[0072] The preparation of aldehydes of formula V is effected
according to methods known from the literature, such as e.g. the
optionally selective alkylation of dihydroxyalkyl-benzaldehydes, as
described by e.g. von Reichstein et al. in Helv. Chim. Acta 18, 816
(1935).
[0073] The compounds of formula VI are commercially available or
can be prepared according to conventional processes known from the
literature.
[0074] For the production of medicaments, the compounds of formula
I can be mixed in a manner known per se with suitable
pharmaceutical carrier substances, aromas, flavorants and colorants
and formed, for example, as tablets or drages or suspended or
dissolved in water or oil, e.g. olive oil, with the addition of
appropriate adjuvants.
[0075] The thiazolidinecarboxylic acids of formula I can be
administered orally and parenterally in liquid or solid form. As
the injection medium there is preferably used water which contains
stabilizing agents, solubilizers and/or buffers which are usual in
the case of injection solutions. Such additives are e.g. tartrate
or borate buffer, ethanol, dimethyl sulphoxide, complex formers
(such as ethylenediaminetetraacetic acid), high molecular weight
polymers (such as liquid polyethylene oxide) for viscosity
adjustment or polyethylene derivatives of sorbitan hydrides.
[0076] Solid carrier materials are e.g. starch, lactose, mannitol,
methylcellulose, talc, highly dispersed silicic acid and high
molecular weight polymers (such as polyethylene glycols). If
desired, preparations suitable for oral administration can contain
flavorants and sweeteners.
[0077] The dosage administered depends on the age, the health and
the weight of the recipient, the extent of the disease, the
additional treatments which may be carried out simultaneously by
the physician and the kind of effect which is desired. Usually, the
daily dosage of active compound amounts to 0.1 to 50 mg/kg body
weight. Normally, 0.5 to 40 mg/kg/day, preferably 1.0 to 20
mg/kg/day, in one or more doses are effective in achieving the
desired results. The active agent can be given in the form of
tablets, capsules or injections.
[0078] The following compounds of formula I are especially
preferred in the scope of the present invention in addition to
those set forth in the Examples:
[0079] 1.
5-[(2,4-Bis-(4-chlorophenylmethoxy)phenyl)methylene]-4-oxo-2-thi-
oxo-3-thiazolidine-acetic acid
[0080] 2.
5-[(2,4-Bis-(4-methylphenylmethoxy)phenyl)methylene]-4-oxo-2-thi-
oxo-3-thiazolidineacetic acid Fp=211.degree. C.
[0081] 3.
5-[(2,4-Bis-(3,4-methylenedioxyphenylmethoxy)phenyl)methylene]-4-
-oxo-2-thioxo-3-thiazolidineacetic acid
[0082] 4.
5-[(2,4-Bis-(2-chlorophenylmethoxy)phenyl)methylene]-4-oxo-2-thi-
oxo-3-thiazolidineacetic acid
[0083] 5.
5-[(2,4-Bis-(3-chlorophenylmethoxy)phenyl)methylene]-4-oxo-2-thi-
oxo-3-thiazolidineacetic acid
[0084] 6.
5-[(2,4-Bis-(3-(4-chlorophenyl)propoxy)phenyl)methylene]-4-oxo-2-
-thioxo-3-thiazolidineacetic acid
[0085] 7. 5-[(2,4-Bis-(4-methoxyphenylmethoxy)phenyl)
methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid
[0086] 8.
5-[(2,4-Bis-(2-phenylethoxy)phenyl)methylene]-4-oxo-2-thioxo-3-t-
hiazolidine-acetic acid
[0087] 9.
5-[(2,4-Bis-(3-phenylpropoxy)phenyl)methylene]-4-oxo-2-thioxo-3--
thiazolidine-acetic acid
[0088] 10.
5-[(2-Phenylmethoxy-4-(3-phenylpropoxy)phenyl)methylene]-4-oxo--
2-thioxo-3-thiazolidineacetic acid
[0089] 11.
5-[(2-(4-Chlorophenylmethoxy)-4-(3-phenylpropoxy)phenyl)methyle-
ne]-4-oxo-2-thioxo-3-thiazolidineacetic acid
[0090] 12.
5-[(2-(2-Thienylmethoxy)-4-(3-phenylpropoxy)phenyl)methylene]-4-
-oxo-2-thioxo-3-thiazolidineacetic acid
[0091] 13.
5-[(2-(2-Pyridylmethoxy)-4-(3-phenylpropoxy)phenyl)methylene]-4-
-oxo-2-thioxo-3-thiazolidineacetic acid
[0092] 14.
2-{5-[(2,4-Bis-benzyloxyphenyl)methylene]-4-oxo-2-thioxo-3-thia-
zolidine}-propionic acid
[0093] 15.
1-{5-[(2,4-Bis-benzyloxyphenyl)methylene]-4-oxo-2-thioxo-3-thia-
zolidine}-propionic acid
[0094] 16.
{5-[(2,4-Bis-benzyloxyphenyl)methylene]-4-oxo-2-thioxo-3-thiazo-
lidine}-phenyl-acetic acid
[0095] 17.
{5-[(2,5-Bis-benzyloxyphenyl)methylene]-4-oxo-2-thioxo-3-thiazo-
lidine}-phenyl-acetic acid
[0096] 18.
{5-[(2,5-Bis-benzyloxyphenyl)methylene]-4-oxo-2-thioxo-3-thiazo-
lidine}-(4-chloro-phenyl)-acetic acid
[0097] 19.
4-{5-[(2,4-Bis-benzyloxyphenyl)methylene]-4-oxo-2-thioxo-3-thia-
zolidine}-butyric acid
[0098] 20.
2-{5-[(2,4-Bis-benzyloxyphenyl)methylene]-4-oxo-2-thioxo-3-thia-
zolidine}-3-phenyl-butyric acid
[0099] 21.
2-{5-[(2,5-Bis-benzyloxyphenyl)methylene]-4-oxo-2-thioxo-3-thia-
zolidine}-3-phenyl-butyric acid
[0100] 22.
5-[(2-Benzyloxy-4-(2-phenyl-5-methyl-4-oxazolylethoxy)phenyl)me-
thylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid
[0101] 23.
5-[(2-(4-Chlorophenylmethoxy)-4-(2-phenyl-5-methyl-4-oxazolylet-
hoxy)phenyl)-methylene]-4-oxo-2-thioxo-3-thiazolidineacetic
acid
[0102] 24.
5-[(2-(2-Thienylmethoxy)-4-(2-phenyl-5-methyl-4-oxazolylethoxy)-
phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid
[0103] 25.
5-[(2-(2-Pyridylmethoxy)-4-(2-phenyl-5-methyl-4-oxazolylethoxy)-
phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid.
EXAMPLE 1
5-[(2,5-Bis-(4-chlorophenylmethoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thia-
zolidineacetic Acid
[0104] 125 mg (0.323 mmol) of
2,5-bis-(4-chlorophenyl-methoxy)benzaldehyde- , 68.3 mg (0.355
mmol) of rhodanine-3-acetic acid, 18 mg (0.125 mmol) of piperidine
acetate and 10 ml of toluene were heated on a water separator under
a nitrogen atmosphere for 4 hours. Subsequently, the reaction
mixture was evaporated, the residue was taken up in ethyl acetate,
washed several times with water, dried and again evaporated. The
residue was triturated with diethyl ether and filtered off under
suction: 125 mg (69%) of the title compound; .sup.1HNMR (DMSO-d6,
250 MHz) .delta. 7.92 (s, 1H), 7.49 (m, 8H), 7.20 (m, 2H), 7.00 (m,
1H), 5.22 (s, 2H), 5.18 (s, 2H), 4.57 (s, 2H); TLC (toluene/methyl
ethyl ketone/glacial acetic acid (72:20:8)): Rf=0.51.
EXAMPLE 2
5-[(2,5-Bis-(4-methylphenylmethoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thia-
zolidineacetic Acid
[0105] Analogously to Example 1, from rhodanineacetic acid and
2,5-bis-(4-methylphenylmethoxy)-benzaldehyde, yield 50%.
[0106] .sup.1HNMR (DMSO-d6, 250 MHz) .delta. 7.95 (s, 1H),
6.95-7.40 (m, 11H), 5.16 (s, 2H), 5.10 (s, 2H), 4.70 (s, 2H), 2.30
(2xs, 6H); TLC (toluene/methyl ethyl ketone/glacial acetic acid
(72:20:8)): Rf=0.53.
EXAMPLE 3
5-[(2,5-Bis-(3,4-methylenedioxyphenylmethoxy)phenyl)methylene]-4-oxo-2-thi-
oxo-3-thiazolidineacetic Acid
[0107] Analogously to Example 1 from rhodanineacetic acid and
2,5-bis-(3,4-methylenedioxy-phenyl-methoxy)benzaldehyde, yield
79%.
[0108] .sup.1HNMR (DMSO-d6, 250 MHz) .delta. 7.92 (s, 1H),
6.85-7.20 (m, 9H), 6.00 (2xs, 4H), 5.10 (s, 2H), 5.01 (s, 2H), 4.60
(s, 2H); TLC (toluene/methyl ethyl ketone/glacial acetic acid
(72:20:8)): Rf=0.52.
EXAMPLE 4
5-[(2,5-Bis-(2-chlorophenylmethoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thia-
zolidineacetic Acid
[0109] Analogously to Example 1, from rhodanineacetic acid and
2,5-bis-(2-chlorophenyl-methoxy)-benzaldehyde, yield 86%.
[0110] .sup.1HNMR (DMSO-d6, 250 MHz) .delta. 8.00 (s, 1H),
6.95-7.65 (m, 11H), 5.29 (s, 2H), 5.21 (s, 2H), 4.70 (s, 2H); TLC
(toluene/methyl ethyl ketone/glacial acetic acid (72:20:8)):
Rf=0.60.
EXAMPLE 5
5-[(2,5-Bis-(3-chlorophenylmethoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thia-
zolidineacetic Acid
[0111] Analogously to Example 1, from rhodanineacetic acid and
2,5-bis-(3-chlorophenyl-methoxy)-benzaldehyde, yield 71%.
[0112] .sup.1HNMR (DMSO-d6, 250 MHz) .delta. 8.00 (s, 1H),
6.95-7.52 (m, 11H), 5.22 (s, 2H), 5.19 (s, 2H), 4.71 (s, 2H); TLC
(toluene/methyl ethyl ketone/glacial acetic acid (72:20:8)):
Rf=0.58.
EXAMPLE 6
5-[(2,5-Bis-(3-(4-chlorophenyl)propoxy)phenyl)methylene]-4-oxo-2-thioxo-3--
thiazolidine-acetic Acid
[0113] Analogously to Example 1, from rhodanineacetic acid and
2,5-bis-(3-(4-chlorophenyl)-propoxy)benzaldehyde, yield 53%.
[0114] .sup.1HNMR (DMSO-d6, 250 MHz) .delta. 8.01 (s, 1H),
6.90-7.70 (m, 11H), 4.75 (s, 2H), 4.08 (t, 2H), 3.98 (t, 2H), 2.74
(2.mu. t, 4H), 2.03 (m, 4H); TLC (toluene/methyl ethyl
ketone/glacial acetic acid (72:20:8)): Rf=0.67.
EXAMPLE 7
5-[(3,4-bis-(4-chlorophenylmethoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thia-
zolidineacetic Acid
[0115] Analogously to Example 1, from rhodanineacetic acid and
3,4-bis-(4-chlorophenyl-methoxy)-benzaldehyde, yield 68%.
[0116] .sup.1HNMR (DMSO-d6, 250 MHz) .delta. 7.79 (s, 1H),
6.75-7.55 (m, 11H), 5.24 (s, 2H), 5.22 (s, 2H), 4.72 (s, 2H); TLC
(toluene/methyl ethyl ketone/glacial acetic acid (72:20:8)):
Rf=0.54.
EXAMPLE 8
5-[(2,5-Bis-(4-methoxyphenylmethoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thi-
azolidine-acetic Acid
[0117] Analogously to Example 1, from rhodanineacetic acid and
2,5-bis-(4-methoxyphenyl-methoxy)benzaldehyde, yield 79%.
[0118] .sup.1HNMR (DMSO-d6, 250 MHz) .delta. 7.95 (s, 1H),
6.80-7.50 (m, 11H), 5.11 (s, 2H), 5.06 (s, 2H), 4.70 (s, 2H), 3.75
(2xs, 6H); TLC (toluene/methyl ethyl ketone/glacial acetic acid
(72:20:8)): Rf=0.62.
EXAMPLE 9
5-[(2,5-Bis-(2-phenylethoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidin-
eacetic Acid
[0119] Analogously to Example 1, from rhodanineacetic acid and
2,5-bis-(2-phenyl-ethoxy)-benzaldehyde, yield 53%.
[0120] .sup.1HNMR (DMSO-d6, 250 MHz) .delta. 7.93 (s, 1H),
6.85-7.30 (m, 13H), 4.75 (s, 2H), 4.10-4.35 (2xt, 4H), 2.95-3.15
(2xt, 4H); TLC (toluene/methyl ethyl ketone/glacial acetic acid
(72:20:8)): Rf=0.50.
EXAMPLE 10
5-[(2,5-Bis-(3-phenylpropoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidi-
neacetic acid
[0121] Analogously to Example 1, from rhodanineacetic acid and
2,5-bis-(3-phenyl-propoxy)-benzaldehyde, yield 44%.
[0122] .sup.1HNMR (DMSO-d6, 250 MHz) .delta. 8.02 (s, 1H),
6.90-7.38 (m, 13H), 4.73 (s, 2H), 4.08 (t, 2H), 3.98 (t, 2H), 2.75
(2xt, 4H), 2.08 (m, 4H); TLC (toluene/methyl ethyl ketone/glacial
acetic acid (72:20:8)): Rf=0.52.
EXAMPLE 11
5-[(2.3-Bis-(3-phenylpropoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidi-
neacetic Acid
[0123] Analogously to Example 1, from rhodanineacetic acid and
2.3-bis-(3-phenyl-propoxy)-benzaldehyde, yield 34%.
[0124] .sup.1HNMR (DMSO-d6, 250 MHz) .delta. 8.06 (s, 1H),
7.00-7.40 (m, 13H), 4.56 (s, 2H), 4.07 (t, 2H), 4.01 (t, 2H),
2.65-2.90 (2xt, 4H), 1.95-2.20 (m, 4H); TLC (toluene/methyl ethyl
ketone/glacial acetic acid (72:20:8)): Rf=0.50.
EXAMPLE 12
5-[(3,4-bis-(3-phenylpropoxy)phenyl)methylene]-4-oxo-2-thioxo-3-thiazolidi-
neacetic Acid
[0125] Analogously to Example 1, from rhodanineacetic acid and
3,4-bis-(3-phenyl-propoxy)-benzaldehyde, yield 68%.
[0126] .sup.1HNMR (DMSO-d6, 250 MHz) .delta. 7.85 (s, 1H),
7.10-7.35 (m, 13H), 4.72 (s, 2H), 4.00-4.20 (m, 4H), 2.70-2.90 (m,
4H), 1.95-2.15 (m, 4H); TLC (toluene/methyl ethyl ketone/glacial
acetic acid (72:20:8)): Rf=0.65.
EXAMPLE 13
5-[(2-Phenylmethoxy-5-(3-phenylpropoxy)phenyl)methylene]-4-oxo-2-thioxo-3--
thiazolidineacetic Acid
[0127] Analogously to Example 1, from rhodanineacetic acid and
2-phenylmethoxy-5-(3-phenyl-propoxy)benzaldehyde, yield 72%.
[0128] .sup.1HNMR (DMSO-d6, 250 MHz) .delta. 8.01 (s, 1H),
6.95-7.40 (m, 13H), 5.15 (s, 2H), 4.72 (s, 2H), 4.08 (t, 2H), 2.75
(t, 2H), 2.00-2.15 (m, 2H); TLC (toluene/methyl ethyl
ketone/glacial acetic acid (72:20:8)): Rf=0.62.
EXAMPLE 14
5-[(2-(4-Chlorophenylmethoxy)-5-(3-phenylpropoxy)phenyl)methylene]-4-oxo-2-
-thioxo-3-thiazolidineacetic Acid
[0129] Analogously to Example 1, from rhodanineacetic acid and
2-(4-chlorophenylmethoxy)-5-(3-phenyl-propoxy)benzaldehyde, yield
90%.
[0130] .sup.1HNMR (DMSO-d6, 250 MHz) .delta. 8.01 (s, 1H),
6.90-7.55 (m, 12H), 5.14 (s, 2H), 4.75 (s, 2H), 4.08 (t, 2H), 2.75
(t, 2H) 2.00-2.15 (m, 2H); TLC (toluene/methyl ethyl ketone/glacial
acetic acid (72:20:8)): Rf=0.56.
EXAMPLE 15
5-[(2-(2-Thienylmethoxy)-5-(3-phenylpropoxy)phenyl)methylene]-4-oxo-2-thio-
xo-3-thiazolidineacetic Acid
[0131] Analogously to Example 1, from rhodanineacetic acid and
2-(2-thienylmethoxy)-5-(3-phenyl-propoxy)benzaldehyde, yield
78%.
[0132] .sup.1HNMR (DMSO-d6, 250 MHz) .delta. 8.05 (s, 1H),
6.65-7.68 (m, 11H), 5.37 (s, 2H), 4.76 (s, 2H), 4.10 (m, 2H), 2.78
(m, 2H), 2.00-2.20 (m, 2H); TLC (toluene/methyl ethyl
ketone/glacial acetic acid (72:20:8)): Rf=0.53.
EXAMPLE 16
5-[(2-(2-Pyridylmethoxy)-5-(3-phenylpropoxy)phenyl)methylene]-4-oxo-2-thio-
xo-3-thiazolidineacetic Acid
[0133] Analogously to Example 1, from rhodanineacetic acid and
2-(2-pyridylmethoxy)-5-(3-phenylpropoxy)benzaldehyde, yield
15%.
[0134] Low resolution mass spectroscopy (ES) m/e 521 (MH+); TLC
(toluene/methyl ethyl ketone/glacial acetic acid (72:20:8)):
Rf=0.56.
EXAMPLE 17
3-{5-[(2,5-Bis-benzyloxyphenyl)methylene]-4-oxo-2-thioxo-3-thiazolidinel}--
propionic Acid
[0135] a)
5-[(2,5-Bis-benzyloxyphenyl)methylene]-4-oxo-2-thioxo-thiazolidi-
ne
[0136] 1.59 g (5 mmol) of 2,5-bis-benzyloxybenzaldehyde, 0.73 g
(5.5 mmol) of rhodanine, 0.29 g (2 mmol) of piperidine acetate and
40 ml of toluene were heated on a water separator under a nitrogen
atmosphere for 1.5 hours. After cooling, the yellow crystals were
filtered off under suction, washed with toluene and diethyl ether
and dried in a vacuum: 1.34 g (62%) of
5-[(2,5-bis-benzyloxyphenyl)methylene]-4-oxo-2-thioxo-thi-
azolidine; .sup.1HNMR (DMSO-d6, 250 MHz) .delta. 13.80 (s, 1H),
7.80 (s, 1H), 6.85-7.50 (m, 13H), 5.19 (s, 2H), 5.10 (s, 2H); TLC
(toluene/methyl ethyl ketone/glacial acetic acid (72:20:8)):
Rf=0.80.
[0137] b) Title Compound
[0138] A mixture of 130 mg (0.3 mmol) of
5-[(2,5-bis-benzyloxyphenyl)methy-
lene]-4-oxo-2-thioxo-thiazolidine, 194 mg (0.7 mmol)of potassium
carbonate, 92 mg (0.6 mmol) of 3-bromo-propionic acid and 2 ml of
dimethylformamide was stirred at 50.degree. C. for 2.5 hours. After
cooling the mixture was treated with water and acidified with
dilute hydrochloric acid. The precipitate was filtered off,
triturated under isopropanol and dried: 54 mg (36%) of the title
compound; .sup.1HNMR (DMSO-d6,250 MHz) .delta. 7.94 (s, 1H),
6.85-7.60 (m, 13H), 5.20 (s, 2H), 5.12 (s, 2H), 4.20 (m, 2H),
2.60-2.80 (m 2H); TLC (toluene/methyl ethyl ketone/glacial acetic
acid (72:20:8)): Rf=0.60.
EXAMPLE 18
4-{5-[(2,5-Bis-benzyloxyphenyl)methylene]-4-oxo-2-thioxo-3-thiazolidine}-b-
utyric Acid
[0139] Analogously to Example 18b, from
5-[(2,5-bis-benzyloxyphenyl)methyl-
ene]-4-oxo-2-thioxo-thiazolidine and 4-brombutyric acid, yield
45%.
[0140] .sup.1HNMR (DMSO-d6, 250 MHz) .delta. 7.94 (s, 1H),
6.90-7.50 (m, 13H), 5.20 (s, 2H), 5.16 (s, 2H), 3.95-4.10 (m, 2H),
2.20-2.40 (m, 2H), 1.70-2.00 (m, 2H); TLC (toluene/methyl ethyl
ketone/glacial acetic acid (72:20:8)): Rf=0.62.
EXAMPLE 19
2-{5-[(2,5-Bis-(4-methylphenylmethoxy)phenyl)methylene]-4-oxo-2-thioxo-3-t-
hiazolidine}-3-phenylpropionic Acid
[0141] Analogously to Example 1, from
2,5-bis-(4-methylphenylmethoxy)benza- ldehyde and
2-(4-oxo-2-thioxo-3-thiazolidine)-3-phenylpropionic acid, yield
90%.
[0142] .sup.1HNMR (DMSO-d6, 250 MHz) .delta. 7.9 (s, 1H), 6.8-7.4
(m, 16H), 5.85 (m, 1H), 5.15 (s, 2H), 5.05 (s, 2H), 3.5 (m, 2H),
2.5 (s, 3H), 2.3 (s, 3H); TLC (toluene/methyl ethyl ketone/glacial
acetic acid (72:20:8)): Rf=0.66.
EXAMPLE 20
2-{5-[(2,5-Bis-(4-methylphenylmethoxy)phenyl)methylene]-4-oxo-2-thioxo-3-t-
hiazolidine}-3-phenylacetic Acid
[0143] Analogously to Example 1, from
2,5-bis-(4-methylphenylmethoxy)benza- ldehyde and
2-(4-oxo-2-thioxo-3-thiazolidine)-2-phenylacetic, yield 67%.
[0144] .sup.1HNMR (DMSO-d6, 250 MHz) .delta. 7.9 (s, 1H), 6.8-7.4
(m, 17H), 5.15 (s, 2H), 5.06 (s, 2H), 2.5 (s, 3H), 2.3 (s, 3H), TLC
(toluene/methyl ethyl ketone/glacial acetic acid 72:20:8)):
Rf=0.55.
EXAMPLE 21
2-{5-[(2,5-Bis-(4-methylphenylmethoxy)phenyl)methylene]-4-oxo-2-thioxo-3-t-
hiazolidine}-propionic Acid
[0145] Analogously to Example 1, from
2,5-bis-(4-methylphenylmethoxy)benza- ldehyde and
2-(4-oxo-2-thioxo-3-thiazolidine)-propionic acid, yield 50%.
[0146] .sup.1HNMR (DMSO-d6,250 MHz) .delta. 7.9 (s, 1H), 6.9-7.4
(m, 11H), 5.6 (q, 1H), 5.12 (s, 2H), 5.08 (s, 2H), 2,5 (s, 3H), 2.3
(s, 3H), 1.52 (d, 3H); TLC (toluene/methyl ethyl ketone/glacial
acetic acid 72:20:8)): Rf=0.58.
EXAMPLE 22
2-{5-[(2,4-Bis-(4-methylphenylmethoxy)phenyl)methylene]-4-oxo-2-thioxo-3-t-
hiazolidine}-2-phenylacetic Acid
[0147] Analogously to Example 1, from
2,4-bis-(4-methylphenylmethoxy)benza- ldehyde and
2-(4-oxo-2-thioxo-3-thiazolidine)-2-phenylacetic acid, yield
84%.
[0148] .sup.1HNMR (DMSO-d6, 250 MHz) .delta. 7.95 (s, 1H), 6.75-7.5
(m, 17H), 5.21 (s, 2H), 5.12 (s, 2H), 2.5 (s, 3H), 2.3 (s, 3H), TLC
(toluene/methyl ethyl ketone/glacial acetic acid 72:20:2)):
Rf=0.30.
EXAMPLE 23
2-{5-[(2,4-Bis-(4-methylphenylmethoxy)phenyl)methylene]-4-oxo-2-thioxo-3-t-
hiazolidine}-3-phenypropionic Acid
[0149] Analogously to Example 1, from
2,4-bis-(4-methylphenylmethoxy)benza- ldehyde and
2-(4-oxo-2-thioxo-3-thiazolidine)-3-phenylpropionic acid, yield
57%.
[0150] .sup.1HNMR (DMSO-d6, 250 MHz) .delta. 7.88 (s, 1H), 6.75-7.4
(m, 16H), 5.85 (m, 1H), 5.20 (s, 2H), 5.15 (s, 2H), 3.45 (m, 2H),
2.5 (s, 3H), 2.3 (s, 3H); TLC (toluene/methyl ethyl ketone/glacial
acetic acid 72:20:2)): Rf=0.27.
EXAMPLE 24
2-{5-[(2,4-Bis-(4-methylphenylmethoxy)phenyl)methylene]-4-oxo-2-thioxo-3-t-
hiazolidine}-2-(4-chlorophenyl)acetic Acid
[0151] Analogously to Example 1, from
2,4-bis-(4-methylphenylmethoxy)benza- ldehyde and
2-(4-oxo-2-thioxo-3-thiazolidine)-2-(4-chlorophenyl)acetic acid,
yield 63%.
[0152] .sup.1HNMR (DMSO-d6,250 MHz) .delta. 7.95 (s, 1H), 6.75-7.55
(m, 16H), 5.21 (s, 2H), 5.15 (s, 2H), 2.5 (s, 3H), 2.3 (s, 3H); TLC
(toluene/methyl ethyl ketone/glacial acetic acid (72:20:2)):
Rf=0.25.
EXAMPLE 25
2-{5-[(2,4-Bis-(4-methylphenylmethoxy)phenyl)methylene]-4-oxo-2-thioxo-3-t-
hiazolidine}-propionic Acid
[0153] Analogously to Example 1, from
2,4-bis-(4-methylphenylmethoxy)benza- ldehyde and
2-(4-oxo-2-thioxo-3-thiazolidine)-propionic acid, yield 56%.
[0154] .sup.1HNMR (DMSO-d6,250 MHz) .delta. 7.93 (s, 1H), 6.75-7.45
(m, 11H), 5.6 (q, 1H), 5.21 (s, 2H), 5.15 (s, 2H), 2.5 (s, 3H); 2.3
(s, 3H), 1.5 (d, 3H); TLC (toluene/methyl ethyl ketone/glacial
acetic acid (72:20:8)): Rf=0.56.
EXAMPLE 26
Biological Activity of the Novel Compounds
[0155] The compound of the invention were tested (ELISA test) as
human urokinase (uPA) inhibitors, which bind to the specific
receptor uPAR mAk (BIO-R.sub.4), in accordance with the procedure
described by Rettenberger et al. In Biol. Chem. Hoppe Seyler 376,
587-94 (1995). The assays are carried out in microtitre plates (96
wells).
[0156] Results:
1 Compound % Inhibition at 1 .mu.g/ml concentration Compound 2 48
Example 2 68 Example 6 57 Example 13 53 Example 15 63 Example 22 60
Example 23 54 Example 24 69
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